Understanding the structure and function of the brain is one of the great scientific problems. Neurodegenerative conditions of the brain are among the most expensive, disruptive, and least well-treated human diseases, arguably because they are not well understood, which precludes a rational approach to treatment. Array Tomography is a new method for tissue imaging with resolution in all three dimensions sufficient to resolve individual synapses and with quantitative characterization of multiple (currently 36) molecular constituents, throughout a 1-mm3 sample. What this means is that it is now possible to construct the wiring diagram of a neural circuit, consisting of a few 100 million to a billion synapses with precise description of the molecular constituents. We believe that this kind of information will enable researchers to begin to comprehend the proper function of neural circuits and, importantly, to begin to understand how it is that the various neurodegenerative processes present and progress. As alluring as this prospect is, Array Tomography has been used in relatively few studies following the inaugural publication in 2007 (Micheva and Smith, 2007), due to the complexity of the method and the cost of establishing it in the lab of an individual investigator. The commercial opportunity is to offer Array Tomography as a service to the research community. We believe this is the best way to bring the power of the method to bear on problems in neuroscience, cancer research, and medical diagnostic and therapeutic development. To that end, in this proposal we seek to refine the procedures developed in the Smith laboratory so that it will be possible to offer array tomography as a service to the academic and industrial communities. Specifically, we propose to develop a single-purpose imaging instrument, including control software that will allow a many-fold increase in tissue slice imaging. In addition, we propose to develop an image storage and retrieval system to enhance the commercial use of array tomography. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases, such as Alzheimer's and Parkinson's are becoming more and more prevalent as the population ages. Efforts to develop treatments for these diseases have been hampered by a lack of technologies that provide "big picture" information about how these diseases progress. We propose to develop a technology for high-resolution microscopic analysis of large brain areas to more fully understand the cellular pathologies caused by these diseases so that more effective treatments can be discovered.